The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice, are incorporated by reference.
Sol-gel derived SiO2 is commonly prepared from alkoxides or inorganic silicates that via hydrolysis form a sol that contains either partly hydrolysed silica species or fully hydrolysed silicic acid. Consequent condensation reactions of SiOH containing species lead to formation of larger silica species with increasing amount of siloxane bonds. Furthermore, the species aggregate, form nanosized particles and/or larger aggregates until a gel is formed. The sols derived from alkoxides provide possibilities to adjust the siloxane bond formations and aggregation due to possibility for partial hydrolysis. Reactions (typically at ≤40° C.) are commonly catalysed either by mineral acids (such as HCl and HNO3) or bases (such as NH3). The formed gel is then aged (typically at ≤40° C.), dried (typically at ≤40° C.) and/or heat-treated (typically at ≤700° C.) to desired form resulting typically in amorphous and porous SiO2. The last step, heat treatment at elevated temperatures (50-700° C.) is typically skipped if the system contains a biologically active agent. The gels that are dried at moderate temperature (at ≤50° C.) are called xerogels (<Gr. xero=dry). Amorphous and porous sol-gel derived SiO2 is known to be biocompatible and known to dissolve in the living tissue as well as in solutions simulating the inorganic part of real human body fluid, e.g. in a water solution buffered to pH 7.4 at 37° C. with or without inorganic salts found in real body fluids.
The terms used for degradation of a material in or in contact with the living organisms, e.g. living tissue or in contact with plants, microbes etc., are numerous. The terms “biodegradable/biodegradation” are often used as a general definition for degradation in or in contact with living organisms. The terms are also used, especially in connection with carbon-based polymers to describe that the degradation mechanism may include both dissolution in body fluids as well as enzymatic degradation of the polymer matrix. Regarding carbon-based polymers, this often means either decrease in molecular weight or mass loss or both. The terms bioresorbable/bioresorption and bioabsorbable/bioabsorption are often used to describe materials degradation in or in contact with the living organism, mostly for implanted biomaterials in living tissue describing a degradation mechanism mainly governed by dissolution in the body fluids or by a mechanism that is not exactly known. Bioresorption is often used for implantable ceramic biomaterials, such as bioactive glasses or sol-gel derived SiO2. The general terms dissolution/soluble in body fluids are often used for biomaterials implanted into the living tissue. The terms (bio)erosion/(bio)erodable are more often in use in drug delivery, especially as it is desirable to distinguish between the mechanisms that control the release. Surface erosion describes a material that is so hydrophobic that water absorption does not occur and dissolution/degradation occurs on the surface and bulk erodable material allow water absorption.
The importance of bioresorbable materials is growing in controlled release of biologically active agents. It is often desirable to administer drugs as implants or as injected matrices, either in order to achieve local and/or more effective results in a desired tissue or a controlled systemic effect. A large potential group of biologically active agents for this purpose is biotechnologically produced drugs. The number of these drugs is growing fast and it is accelerated by the successful research on the human genome. New biotech drugs are typically larger in size, such as peptides, proteins and polysaccharides, and direct oral administration is difficult due to intestinal decomposition. In addition, bioresorbable matrices are potential materials for optimising the administration of small molecules by implantation, e.g, to avoid administration several times a day or to optimise the patient docility for drug therapy. In addition, bioresorbable materials are potential matrices as it is desirable to avoid extra removal operations that are commonly done for biostable delivery matrices, (such as PDMS, polydimethylsiloxane). Materials having pore sizes between 1-100 nm are in the same order of magnitude as the size of many peptides and proteins, but solely diffusion-controlled release is often far from the optimal.
WO 93/04196 by Zink et al. discloses the idea of encapsulating enzymes in a porous transparent glass, prepared with a sol-gel method. The purpose is to immobilize enzymes in the pore structure and thus, the release of the enzymes is to be avoided. These porous, transparent glasses can be used to prepare sensors for qualitatively and quantitatively detecting both organic and inorganic compounds, which react with the entrapped material. The pore radius in these glasses is so small (under about 4 nm) that the entrapped biologically active materials cannot diffuse out from the glass.
WO96/03117 by Ducheyne et al. discloses controlled release carriers, where biologically active molecules are incorporated within the matrix of a silica-based glass. Here, silica-based glasses are typically multicomponent glasses, and 100% SiO2 is a special case, with a very poor dissolution. The release of the biologically active molecules from the carrier is claimed to occur primarily by diffusion through the pore structure and bioresorption is not mentioned to affect the release of biologically active agents.
WO 97/45367 by Ahola et al. describes controlled dissolvable silica-xerogels prepared via a sol-gel process. The preparation of dissolvable oxides (silica xerogels) is carried out by simultaneous gelation and evaporation and mainly concerns small particles made by spray-drying or fibres made by drawing. WO 01/13924 by Ahola et al. describes controlled release of a biologically active agent from a sol-gel derived silica xerogel. These inventions provide sustained and/or controlled release delivery devices for biologically active agents, but they do not give methods for adjusting bioresorption or merely give very limited means for adjusting bioresorption.
WO 00/50349 by Jokinen et al. and WO 01/40556 by Peltola et al. disclose methods for preparation of sol-gel derived silica fibres. WO 00/50349 discloses a method for adjusting the biodegradation rate of the fibres by controlling the viscosity of the spinning process. WO 01/40556 discloses a method for preparing a bioactive sol-gel derived silica fibre.
WO 02/080977 by Koskinen et al. discloses a method for preparation of a biodegradable silica xerogel comprising infecting and/or transfecting viruses.
The prior art does not provide versatile means for preparing sol-gel derived SiO2 with tailored bioresorption rates. In particular it does not provide means for preparing sol-gel derived SiO2 with a very fast bioresorption rate.